The YIN/YANG transcriptional interplay between melanoma invasion/proliferation is steered by the STAT3/MITF dualism
Malignant melanomas display a high tendency for metastasis. The required steps for tumor cells to expand, migrate and invade distant organs are well-known, but genetic studies to understand these key cancer progression phases lack behind.
A key transcription factor controlling melanoma fate is the melanocytes inducing transcription factor (MITF). High expression leads to a proliferative signature, whereas low expression is associated with an invasive phenotype in melanoma. Another important transcription factor for tumor fate is signal transducer and activator of transcription 3 (STAT3), but it's in vivo role in melanoma is far less clear.
We started by using a metastatic mouse melanoma model to investigate the role of STAT3 in this process. We identified STAT3 as a critical regulator of MITF expression levels in melanoma. Mechanistically we have shown that the direct STAT3 target genes and transcription factors CEBPA and CEBPB bind to the promoter region of MITF suppressing its transcription. We could show that this process does not only occur in a mouse model for melanoma, but also in human melanoma cells. A vice versa correlation can also be seen on mRNA and protein level in melanoma patient sample analysis. Overall, the YIN/YANG cross-regulation of STAT3 and MITF is not a black and white regulatory system, but it is more a dynamic process where distinct malignancy associated phenotypes become up- and down-regulated. For example, when analyzing melanoma patient groups, the high risk group shows decreased STAT3, CEBPA and CEBPB, but increased MITF levels, indicating also higher proliferation for a certain time period. Future studies will have to address the role of STAT3 and MITF in senescence programs of melanocytes, telomere stability, sex hormone, cytokine and growth factor action as well as the diverse genetic association of melanoma clones with the immune cell status. For patient therapy, targeting both STAT3 and MITF could display merit and we are in the era to develop an armory of new inhibitors targeting also transcription factors with small molecular weight compounds.
We conclude that these novel findings have important consequences for melanoma diagnosis and therapy. Monitoring the STAT3 activation status in melanoma cells can be a surrogate marker to estimate the current phase of melanoma progression. Regarding patient therapy, high STAT3 levels indicate tumor cell de-differentiation and a low proliferative status. Hence, novel therapeutic strategies could be pioneered, which on the one hand enhance tumor cell differentiation by elevating MITF expression and on the other hand also targeting cycling cells to arrest proliferation (1). In conclusion, we propose that monitoring STAT3 levels in melanoma adds valuable information for clinical decision-making.
- Mirea, M. A., S. Eckensperger, M. Hengstschlager, and M. Mikula. 2020. Insights into Differentiation of Melanocytes from Human Stem Cells and Their Relevance for Melanoma Treatment. Cancers (Basel). 2020;12:2508–19.